The long noncoding RNA H19 regulates tumor plasticity in neuroendocrine prostate cancer

Neha Singh; Varune R. Ramnarine; Jin H. Song; Ritu Pandey; Sathish K.R. Padi; Mannan Nouri; Virginie Olive; Maxim Kobelev; Koichi Okumura; David McCarthy; Michelle M. Hanna; Piali Mukherjee; Belinda Sun; Benjamin R. Lee; J. Brandon Parker; Debabrata Chakravarti; Noel A. Warfel; Muhan Zhou; Jeremiah J. Bearss; Ewan A. Gibb; Mohammed Alshalalfa; R. Jefferey Karnes; Eric J. Small; Rahul Aggarwal; Felix Feng; Yuzhuo Wang; Ralph Buttyan; Amina Zoubeidi; Mark Rubin; Martin Gleave; Frank J. Slack; Elai Davicioni; Himisha Beltran; Colin Collins; Andrew S. Kraft

doi:10.1038/s41467-021-26901-9

The long noncoding RNA H19 regulates tumor plasticity in neuroendocrine prostate cancer

Neha Singh, Varune R. Ramnarine, Jin H. Song, Ritu Pandey, Sathish K.R. Padi, Mannan Nouri, Virginie Olive, Maxim Kobelev, Koichi Okumura, David McCarthy, Michelle M. Hanna, Piali Mukherjee, Belinda Sun, Benjamin R. Lee, J. Brandon Parker, Debabrata Chakravarti, Noel A. Warfel, Muhan Zhou, Jeremiah J. Bearss, Ewan A. GibbMohammed Alshalalfa, R. Jefferey Karnes, Eric J. Small, Rahul Aggarwal, Felix Feng, Yuzhuo Wang, Ralph Buttyan, Amina Zoubeidi, Mark Rubin, Martin Gleave, Frank J. Slack, Elai Davicioni, Himisha Beltran, Colin Collins, Andrew S. Kraft

Urology

Research output: Contribution to journal › Article › peer-review

Abstract

Neuroendocrine (NE) prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (PCa) arising either de novo or from transdifferentiated prostate adenocarcinoma following androgen deprivation therapy (ADT). Extensive computational analysis has identified a high degree of association between the long noncoding RNA (lncRNA) H19 and NEPC, with the longest isoform highly expressed in NEPC. H19 regulates PCa lineage plasticity by driving a bidirectional cell identity of NE phenotype (H19 overexpression) or luminal phenotype (H19 knockdown). It contributes to treatment resistance, with the knockdown of H19 re-sensitizing PCa to ADT. It is also essential for the proliferation and invasion of NEPC. H19 levels are negatively regulated by androgen signaling via androgen receptor (AR). When androgen is absent SOX2 levels increase, driving H19 transcription and facilitating transdifferentiation. H19 facilitates the PRC2 complex in regulating methylation changes at H3K27me3/H3K4me3 histone sites of AR-driven and NEPC-related genes. Additionally, this lncRNA induces alterations in genome-wide DNA methylation on CpG sites, further regulating genes associated with the NEPC phenotype. Our clinical data identify H19 as a candidate diagnostic marker and predictive marker of NEPC with elevated H19 levels associated with an increased probability of biochemical recurrence and metastatic disease in patients receiving ADT. Here we report H19 as an early upstream regulator of cell fate, plasticity, and treatment resistance in NEPC that can reverse/transform cells to a treatable form of PCa once therapeutically deactivated.

Original language	English (US)
Article number	7349
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-26901-9
State	Published - Dec 2021

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Singh, N., Ramnarine, V. R., Song, J. H., Pandey, R., Padi, S. K. R., Nouri, M., Olive, V., Kobelev, M., Okumura, K., McCarthy, D., Hanna, M. M., Mukherjee, P., Sun, B., Lee, B. R., Parker, J. B., Chakravarti, D., Warfel, N. A., Zhou, M., Bearss, J. J., ... Kraft, A. S. (2021). The long noncoding RNA H19 regulates tumor plasticity in neuroendocrine prostate cancer. Nature communications, 12(1), Article 7349. https://doi.org/10.1038/s41467-021-26901-9

Singh, N, Ramnarine, VR, Song, JH, Pandey, R, Padi, SKR, Nouri, M, Olive, V, Kobelev, M, Okumura, K, McCarthy, D, Hanna, MM, Mukherjee, P, Sun, B, Lee, BR, Parker, JB, Chakravarti, D, Warfel, NA, Zhou, M, Bearss, JJ, Gibb, EA, Alshalalfa, M, Karnes, RJ, Small, EJ, Aggarwal, R, Feng, F, Wang, Y, Buttyan, R, Zoubeidi, A, Rubin, M, Gleave, M, Slack, FJ, Davicioni, E, Beltran, H, Collins, C & Kraft, AS 2021, 'The long noncoding RNA H19 regulates tumor plasticity in neuroendocrine prostate cancer', Nature communications, vol. 12, no. 1, 7349. https://doi.org/10.1038/s41467-021-26901-9

@article{764180ba2eb5416d9450095ad43bdb46,

title = "The long noncoding RNA H19 regulates tumor plasticity in neuroendocrine prostate cancer",

abstract = "Neuroendocrine (NE) prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (PCa) arising either de novo or from transdifferentiated prostate adenocarcinoma following androgen deprivation therapy (ADT). Extensive computational analysis has identified a high degree of association between the long noncoding RNA (lncRNA) H19 and NEPC, with the longest isoform highly expressed in NEPC. H19 regulates PCa lineage plasticity by driving a bidirectional cell identity of NE phenotype (H19 overexpression) or luminal phenotype (H19 knockdown). It contributes to treatment resistance, with the knockdown of H19 re-sensitizing PCa to ADT. It is also essential for the proliferation and invasion of NEPC. H19 levels are negatively regulated by androgen signaling via androgen receptor (AR). When androgen is absent SOX2 levels increase, driving H19 transcription and facilitating transdifferentiation. H19 facilitates the PRC2 complex in regulating methylation changes at H3K27me3/H3K4me3 histone sites of AR-driven and NEPC-related genes. Additionally, this lncRNA induces alterations in genome-wide DNA methylation on CpG sites, further regulating genes associated with the NEPC phenotype. Our clinical data identify H19 as a candidate diagnostic marker and predictive marker of NEPC with elevated H19 levels associated with an increased probability of biochemical recurrence and metastatic disease in patients receiving ADT. Here we report H19 as an early upstream regulator of cell fate, plasticity, and treatment resistance in NEPC that can reverse/transform cells to a treatable form of PCa once therapeutically deactivated.",

author = "Neha Singh and Ramnarine, {Varune R.} and Song, {Jin H.} and Ritu Pandey and Padi, {Sathish K.R.} and Mannan Nouri and Virginie Olive and Maxim Kobelev and Koichi Okumura and David McCarthy and Hanna, {Michelle M.} and Piali Mukherjee and Belinda Sun and Lee, {Benjamin R.} and Parker, {J. Brandon} and Debabrata Chakravarti and Warfel, {Noel A.} and Muhan Zhou and Bearss, {Jeremiah J.} and Gibb, {Ewan A.} and Mohammed Alshalalfa and Karnes, {R. Jefferey} and Small, {Eric J.} and Rahul Aggarwal and Felix Feng and Yuzhuo Wang and Ralph Buttyan and Amina Zoubeidi and Mark Rubin and Martin Gleave and Slack, {Frank J.} and Elai Davicioni and Himisha Beltran and Colin Collins and Kraft, {Andrew S.}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41467-021-26901-9",

language = "English (US)",

volume = "12",

journal = "Nature communications",

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T1 - The long noncoding RNA H19 regulates tumor plasticity in neuroendocrine prostate cancer

AU - Singh, Neha

AU - Ramnarine, Varune R.

AU - Song, Jin H.

AU - Pandey, Ritu

AU - Padi, Sathish K.R.

AU - Nouri, Mannan

AU - Olive, Virginie

AU - Kobelev, Maxim

AU - Okumura, Koichi

AU - McCarthy, David

AU - Hanna, Michelle M.

AU - Mukherjee, Piali

AU - Sun, Belinda

AU - Lee, Benjamin R.

AU - Parker, J. Brandon

AU - Chakravarti, Debabrata

AU - Warfel, Noel A.

AU - Zhou, Muhan

AU - Bearss, Jeremiah J.

AU - Gibb, Ewan A.

AU - Alshalalfa, Mohammed

AU - Karnes, R. Jefferey

AU - Small, Eric J.

AU - Aggarwal, Rahul

AU - Feng, Felix

AU - Wang, Yuzhuo

AU - Buttyan, Ralph

AU - Zoubeidi, Amina

AU - Rubin, Mark

AU - Gleave, Martin

AU - Slack, Frank J.

AU - Davicioni, Elai

AU - Beltran, Himisha

AU - Collins, Colin

AU - Kraft, Andrew S.

PY - 2021/12

Y1 - 2021/12

N2 - Neuroendocrine (NE) prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (PCa) arising either de novo or from transdifferentiated prostate adenocarcinoma following androgen deprivation therapy (ADT). Extensive computational analysis has identified a high degree of association between the long noncoding RNA (lncRNA) H19 and NEPC, with the longest isoform highly expressed in NEPC. H19 regulates PCa lineage plasticity by driving a bidirectional cell identity of NE phenotype (H19 overexpression) or luminal phenotype (H19 knockdown). It contributes to treatment resistance, with the knockdown of H19 re-sensitizing PCa to ADT. It is also essential for the proliferation and invasion of NEPC. H19 levels are negatively regulated by androgen signaling via androgen receptor (AR). When androgen is absent SOX2 levels increase, driving H19 transcription and facilitating transdifferentiation. H19 facilitates the PRC2 complex in regulating methylation changes at H3K27me3/H3K4me3 histone sites of AR-driven and NEPC-related genes. Additionally, this lncRNA induces alterations in genome-wide DNA methylation on CpG sites, further regulating genes associated with the NEPC phenotype. Our clinical data identify H19 as a candidate diagnostic marker and predictive marker of NEPC with elevated H19 levels associated with an increased probability of biochemical recurrence and metastatic disease in patients receiving ADT. Here we report H19 as an early upstream regulator of cell fate, plasticity, and treatment resistance in NEPC that can reverse/transform cells to a treatable form of PCa once therapeutically deactivated.

AB - Neuroendocrine (NE) prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (PCa) arising either de novo or from transdifferentiated prostate adenocarcinoma following androgen deprivation therapy (ADT). Extensive computational analysis has identified a high degree of association between the long noncoding RNA (lncRNA) H19 and NEPC, with the longest isoform highly expressed in NEPC. H19 regulates PCa lineage plasticity by driving a bidirectional cell identity of NE phenotype (H19 overexpression) or luminal phenotype (H19 knockdown). It contributes to treatment resistance, with the knockdown of H19 re-sensitizing PCa to ADT. It is also essential for the proliferation and invasion of NEPC. H19 levels are negatively regulated by androgen signaling via androgen receptor (AR). When androgen is absent SOX2 levels increase, driving H19 transcription and facilitating transdifferentiation. H19 facilitates the PRC2 complex in regulating methylation changes at H3K27me3/H3K4me3 histone sites of AR-driven and NEPC-related genes. Additionally, this lncRNA induces alterations in genome-wide DNA methylation on CpG sites, further regulating genes associated with the NEPC phenotype. Our clinical data identify H19 as a candidate diagnostic marker and predictive marker of NEPC with elevated H19 levels associated with an increased probability of biochemical recurrence and metastatic disease in patients receiving ADT. Here we report H19 as an early upstream regulator of cell fate, plasticity, and treatment resistance in NEPC that can reverse/transform cells to a treatable form of PCa once therapeutically deactivated.

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The long noncoding RNA H19 regulates tumor plasticity in neuroendocrine prostate cancer

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